Obesity has reached epidemic proportions across the world, particularly in prosperous nations like the United States. Having a body mass index (BMI) > 30 kg/m2 clinically defines an individual as obese and significantly increases that individual's risk of developing other co-morbidities that comprise the deadly quartet of metabolic syndrome, including type II diabetes, hypertension, and hyperlipidemia. In the absence of efficient intervention strategies for curbing obesity, the promotion of non-shivering thermogenesis (NST) has re- emerged as a potentially viable approach. NST expends energy by generating heat from peripheral tissues, particularly brown adipose tissue (BAT). Despite the controversy surrounding the importance of BAT in the control of body weight in adult humans, BAT size has been found to correlate negatively with body mass index and thus central regulators of BAT thermogenesis may be potential targets for anti-obesity drugs. A number of reports suggest that leptin, a pleiotropic adipocyte-derived hormone, may regulate body weight, in part, by central thermoregulatory mechanisms. Indeed, leptin-responsive neurons in the dorsomedial hypothalamus (DMH) have been shown to recapitulate such central thermoregulatory pathways. Accordingly, we hypothesize that DMH leptin receptor (LepRb) expressing neurons regulate energy expenditure via BAT NST and represent an indirect means of body weight control. Here, the proposed studies will examine LepRb expressing neurons in the DMH of mice using molecular biological state-of-the-art tools that have hitherto not been used in the thermoregulation research field, including pharmacogenetics and optogenetics. The objective of these studies is to advance our understanding of NST and facilitate the identification of novel, druggable targets for the treatment of obesity. This objective will be accomplished by modulating the neuronal activity of DMH LepRb expressing neurons in vivo to study their effect on body weight/composition, energy expenditure, and body temperature during nutritional challenges in two aims. SPECIFIC AIM I will examine the relationship between DMH leptinergic neuronal activity and body weight/composition by using pharmacogenetic designer receptors exclusively activated by designer drugs (DREADD) technology. SPECIFIC AIM II will investigate if DMH LepRb expressing neurons integrate other nutrient signals that also regulate energy expenditure by using optogenetic technology. PUBLIC HEALTH RELEVANCE: Current obesity therapies have not been successful, demonstrated by the ongoing dramatic rise in obesity. It is becoming increasingly apparent that there is need for a better understanding of the mechanisms controlling body weight. In humans and other mammals, brown fat cells generate heat and maintain body temperature, a process which burns white fat as a fuel source. Leptin, a hormone produced by fat cells, has been suggested to play a role in this process. This proposal investigates how leptin causes the brain to stimulate heat production from brown fat cells and how this process can used to promote weight loss.